Understanding longitudinal microbiome change in relation to immunologic outcomes in pediatric SCT recipients.

了解儿科 SCT 受者的纵向微生物组变化与免疫结果的关系。

基本信息

批准号：
10543190
负责人：
Caitlin Walfoort Elgarten
金额：
$ 18.57万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10543190
关键词：
Acute Graft Versus Host Disease Address Advisory Committees Allogenic Anti-Infective Agents Antibiotics Behavior Bioinformatics Biological Markers Biology Carbapenems Cell physiology Cells Child Childhood Childhood Leukemia Clinical Clinical Research Complex Concentration measurement Data Development Dimensions Disease Drug Kinetics Drug Targeting Engraftment Ensure Environment Epidemiologist Epidemiology Event Exposure to Foundations Future Gastrointestinal tract structure Goals Healthcare Hematological Disease Hematopoietic System Hemoglobinopathies Human Immune Immune System Diseases Immune system Immunity Immunologic Deficiency Syndromes Immunologics Individual Infection Intervention Intervention Studies Investigation Kinetics Knowledge Leukocytes Life Link Longitudinal Studies Longitudinal cohort Lymphopenia Measurement Measures Mediating Mentored Patient-Oriented Research Career Development Award Mentorship Metagenomics Methods Modeling Nature Neutropenia Outcome Pathogenesis Patient-Focused Outcomes Patients Pediatric Hospitals Pediatric Oncologist Pediatric Oncology Group Pediatric cohort Pennsylvania Peripheral Pharmaceutical Preparations Pharmacoepidemiology Philadelphia Physicians Physiological Population Prospective cohort Quality of life Recovery Research Research Personnel Research Project Grants Residual state Resources Risk Sampling Scientist Signal Transduction Statistical Methods Stem cell transplant Supportive care System Systems Development Therapeutic Time Training Transplant Recipients Transplantation and Immune System Universities Validation Work adverse outcome behavioral study bone marrow failure syndrome career clinically relevant clinically significant cohort deep sequencing experience falls graft vs host disease host microbiome immune reconstitution improved infection risk interpatient variability kinetic model leukemia longitudinal analysis microbiome microbiome analysis microbiome research microbiome sequencing microbiota neutrophil novel marker patient oriented research patient variability pharmacodynamic model pharmacologic prevent rational design response skills stem cells success therapy design

项目摘要

PROJECT SUMMARY/ABSTRACT This Mentored Patient-Oriented Research Career Development Award proposal will provide didactic and experiential training, expert mentorship, and an exceptional research environment to facilitate Dr. Caitlin Elgarten's development as an independent clinician scientist. Dr. Elgarten's long-term career goal is to develop strategies that use targeted measurement and manipulation of the microbiome to predict and prevent adverse outcomes of pediatric stem cell transplant (SCT). Although SCT offers a chance for cure for more than 1,500 children each year with life-threatening disorders of the hematologic and immune systems, the success of this treatment is limited by aberrant and/or delayed recovery of the new immune system leading to graft-versus-host disease (GVHD), serious infection and reduced survival. In this proposal, Dr. Elgarten will leverage data from three pediatric cohorts to characterize the disruption of the gastrointestinal tract microbiome that occurs during SCT. She will define the microbiome features that associate with acute GVHD and peripheral immune cell recovery, and identify the pharmacologic drivers of clinically relevant microbiome disruption. Through the adaptation of non-linear mixed effects models for repeated measures to model the multidimensional and highly dynamic nature of the microbiome, this study will deliver a greater understanding of the causal association of the microbiome and immune events after SCT. In doing so, this work will lay the foundation for identification of novel biomarkers and the rational design of interventions to improve SCT outcomes. Execution of these aims will also provide the candidate with essential experience in conducting observational microbiome research and with critical training in the advanced bioinformatics and statistical methods necessary to study the interaction of the microbiome, pharmacologic exposures and clinical factors that define risk for adverse outcomes after SCT. The candidate is a pediatric oncologist and SCT physician with formal training in pharmacoepidemiology and a background in clinical research focused on supportive care in SCT. She aspires to bring her perspective as a clinician and epidemiologist to the study of longitudinal microbiome change in this complex clinical scenario. Dr. Elgarten's goals for the K23 program are: 1) conduct a patient-oriented research project that will yield clinically meaningful results, 2) acquire bioinformatics skills for the analysis of microbiome sequencing data, and 3) develop a platform for analysis of longitudinal microbiome data in SCT based on non-linear mixed effects models for repeated measures. She has assembled a strong mentorship and advisory team, led by Dr. Brian Fisher, and inclusive of national experts in microbiome-host biology, deep sequencing methods and bioinformatics, quantitative model-based methods, and translational epidemiology. This guidance, combined with the extensive resources available at the Children's Hospital of Philadelphia and the University of Pennsylvania, will ensure the accomplishment of the proposed research and training goals and Dr. Elgarten's successful transition to independent investigator.

项目概要/摘要这项以患者为导向的研究职业发展奖提案将提供教学和指导体验式培训、专家指导和卓越的研究环境为凯特琳博士提供便利埃尔加滕作为一名独立临床科学家的发展。 Elgarten 博士的长期职业目标是发展使用微生物组的有针对性的测量和操作来预测和预防不良反应的策略儿科干细胞移植（SCT）的结果。尽管 SCT 为超过 1,500 名患者提供了治愈的机会每年都有儿童患有危及生命的血液和免疫系统疾病，这项研究的成功治疗受到新免疫系统异常和/或延迟恢复的限制，导致移植物抗宿主疾病（GVHD）、严重感染和生存率降低。在这项提案中，埃尔加滕博士将利用来自三个儿科队列来描述胃肠道微生物群的破坏干细胞移植。她将定义与急性 GVHD 和外周免疫细胞相关的微生物组特征恢复，并确定临床相关微生物组破坏的药理学驱动因素。通过非线性混合效应模型的适应重复测量来模拟多维和高度微生物组的动态性质，这项研究将更好地理解微生物组的因果关系 SCT 后的微生物组和免疫事件。这样做，这项工作将为小说的鉴定奠定基础。生物标志物和合理设计干预措施以改善 SCT 结果。这些目标的实现也将为候选人提供进行观察性微生物组研究的重要经验以及研究生物信息学和统计方法的相互作用所必需的关键培训定义 SCT 后不良结果风险的微生物组、药物暴露和临床因素。候选人是一名儿科肿瘤学家和 SCT 医生，接受过药物流行病学方面的正规培训，并具有专注于 SCT 支持护理的临床研究背景。她渴望将自己的观点带入临床医生和流行病学家在这种复杂的临床情况下研究纵向微生物组的变化。博士。 Elgarten 的 K23 计划目标是：1）开展以患者为导向的研究项目，该项目将产生临床成果有意义的结果，2) 获得分析微生物组测序数据的生物信息学技能，以及 3) 开发基于非线性混合效应模型的 SCT 纵向微生物组数据分析平台用于重复测量。她组建了一支由 Brian Fisher 博士领导的强大的指导和咨询团队，包括微生物组-宿主生物学、深度测序方法和生物信息学方面的国家专家，基于定量模型的方法和转化流行病学。该指南结合广泛的费城儿童医院和宾夕法尼亚大学的可用资源将确保完成拟议的研究和培训目标以及埃尔加滕博士成功过渡到独立调查员。